Submissions for variant NM_015102.5(NPHP4):c.1196A>G (p.Glu399Gly)

gnomAD frequency: 0.00020  dbSNP: rs117898549

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000340961	SCV000358535	likely benign	Senior-Loken syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000389927	SCV000358536	likely benign	Nephronophthisis 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000766889	SCV000618972	uncertain significance	not provided	2017-07-18	criteria provided, single submitter	clinical testing	The c.1196A>G variant in the NPHP4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1196A>G variant is observed in 82/8578 (0.96%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). In-silico splice models predict that c.1196A>G may create a cryptic splice acceptor site in exon 10 that could supplant the natural splice acceptor site. However, in the absence of RNA/functional studies, the actual effect of the c.1196A>G change in this individual is unknown. If c.1196A>G does not alter splicing, it will result in the E399G missense change.The E399G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.1196A>G as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000523327	SCV000701723	likely benign	not specified	2016-09-28	criteria provided, single submitter	clinical testing
Invitae	RCV001257066	SCV001004822	benign	Nephronophthisis	2024-01-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294254	SCV002587606	uncertain significance	Kidney disorder	2017-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930241	SCV004740961	benign	NPHP4-related condition	2019-10-01	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).